1. Field of the invention
This invention relates to indolecarboxamide derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to fused indolecarboxamides such as carbozolecarboxamides, tetrahydrocarbazolecarboxamides, and fused cycloalkylindolecarboxamides, and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment or prevention of various neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.3 receptor subtype has recently been identified (Sokoloff et al., Nature, 347, 146 (1990)). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.3 receptor may play a major role in the etiology of schizophrenia. Selective D.sub.3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D.sub.3 receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D.sub.3 receptors.
U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides said to have affinity at dopamine D.sub.3 receptors. The compounds of the present invention differ significantly from this prior art in that they possess a dibenzofurancarboxamide substructure.
U.S. Pat. No. 3,932,456 discloses compounds of the formula: ##STR3## wherein each of R.sub.1 and R.sub.2 is hydrogen, (lower)alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group, or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached is pyrrolidino, piperidino, N-(lower) alkylpiperazino, or morpholino; each A is alkylene of 2 to about 8 carbon atoms and separates its adjacent Y and amino nitrogen by an alkylene chain of at least 2 carbon atoms; each Y is oxygen, or N-R wherein R is hydrogen, methyl or ethyl; and R.sub.3 is hydrogen or (lower) primary or secondary alkyl; or a pharmaceutically acceptable acid addition salt thereof.
These compounds are said to be useful as pharmaceuticals for preventing or inhibiting a viral infection.
International application WO94/14773 discloses compounds said to have affinity for the 5-HT.sub.1 -like receptor and utility in the treatment of migraine. The compounds disclosed in that application have the following formula: ##STR4## wherein R.sub.1 represents halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, NO.sub.2, --NR.sub.4 R.sub.5, R.sub.4 R.sub.5 NCO(CH2).sub.m --, R.sub.4 R.sub.5 NSO.sub.2 (CH2).sub.m --, R.sub.6 CONH(CH2).sub.m -- or R.sub.7 SO.sub.2 (CH2).sub.m --; R.sub.4 and R.sub.5 each independently represent hydrogen or C.sub.1-4 alkyl or N.sub.4 R.sub.5 represents a 5- to 7-member heterocyclic ring; R.sub.6 represents hydrogen or C.sub.1-4 alkyl; R.sub.7 represents C.sub.1-4 alkyl; m is zero, 1, or 2; n is zero or 1 to 5; R.sub.2 and R.sub.3 each independently represent hydrogen, C.sub.1-6 alkyl or benzyl or --NR.sub.2 R.sub.3 represents a pyrrolidino, piperidino or hexahydroazepino ring; and A represents a bond, a C.sub.1-5 alkylene chain or a C.sub.3-5 alkenyl chain wherein the double bond is not adjacent the nitrogen atom.
Murray et al., Bioorg. Med. Chem. Let., 5: 219 (1995), describe 4-carboxamidobiphenyls said to have affinity at dopamine D.sub.3 receptors.